ETS-responsive elements are known to be involved in retroviral long terminal repeat (LTR)- dependent expression in animals and man, and we have been characterizing the potential for ERF as an antiviral agent, and its effect on ETS-dependent viral functions. Expression of the ETS1/ETS2-dependent transcriptional inhibitor gene, ERF, failed to block erythropoietin (EPO)- dependent proliferation of ME26-infected, gag-myb-ets-expressing FDC-P2 cells. Since we had previously shown that ERF could inhibit the gag-myb-ets-dependent ability of ME26 to abrogate the serum-dependence and reduce the murine leukemia virus-dependent expression of ME26 viral RNA in NIH3T3 fibroblasts, our results may suggest that the fusion oncogene acts through different mechanisms, or requires different levels of ETS function in fibroblasts and FDC-P2 cells. In contrast to the lack of response to ERF, FDC-P2 (ME26) cell proliferation in EPO was blocked by superinfection with an ERG-B/FLI-1-expressing retroviral construct, but not by one expressing the inhibitory domain of ERF fused to the DNA-binding domain of ERG-B/FLI-1. Cells expressing ERG-B/FLI-1 showed increased expression of erythropoietin receptor-specific mRNA and beta-globin mRNA, but underwent apoptotic cell death within 48 hours of the shift from IL-3 to EPO-containing media.